Alkoxycoumarins substituted by a heterocyclic radical, their preparation and therapeutic agents containing these compounds

ABSTRACT

An alkoxycoumarin substituted by a heterocyclic radical, or the formula ##STR1## R 1  and R 2  independently of one another are each hydrogen, C 1  -C 5  -alkyl, trifluoromethyl, phenyl or halogen, or together form a C 3  -C 5  -alkylene chain, R 3  is C 1  -C 5  -alkyl or halogen, n is an integer of from 0 to 3, R 4  is hydrogen or C 1  -C 4  -alkyl and Het is one of the following heterocyclic radicals: ##STR2##

This application is a continuation of application Ser. No. 07/725,690, filed on Jul. 3, 1991, now abandoned which is a divisional application of Ser. No. 07/417,451, filed Oct. 5, 1989, now U.S. Pat. No. 5,073,563.

The present invention relates to novel alkoxycoumarins substituted by a heterocyclic radical, of the general formula I, their preparation and therapeutic agents which contains these compounds and two known compounds as the active ingredient, in particular for the treatment of disorders of the central nervous system.

Krishna Murthy et al., Indian J. Chem. 10 (1972), 38-40 have tested 4-methyl-7-(3-phenylisoxazol-5-yl-methoxy)-coumarin for fungicidal and bacteriostatic action with little or no success. Apart from this compound, the class of compounds described here is novel, as is the therapeutic use of the novel compound.

It is an object of the present invention to provide novel therapeutic agents, in particular for the treatment of disorders of the central nervous system.

We have found that this object is achieved by the novel compounds of the general formula I as claimed in claim 1, the preparation process as claimed in claim 2 and the therapeutic agents as claimed in claims 3 and 4.

In the general formula I ##STR3## R¹ and R² may be identical or different and are each hydrogen, C₁ -C₅ -alkyl, CF₃, phenyl or halogen, or R¹ and R² together may form a common chain of 3 to 5 carbon atoms, R³ is C₁ -C₅ -alkyl or halogen, n is an integer of from 0 to 3, R⁴ is hydrogen or C₁ -C₄ -alkyl and Het is one of the following heterocyclic radicals: ##STR4## where X is oxygen or sulfur, R⁵ is unsubstituted or C₁ -C₄ -alkoxy-substituted C₁ -C₁₀ -alkyl, 5-membered or 6-membered oxacycloalkyl, C₃ -C₇ -cycloalkyl, benzyl, phenyl which is unsubstituted or substituted by halogen or NO₂, a pyridine ring, C₁ -C₅ -alkoxycarbonyl or perfluoro-C₁ -C₂ -alkyl, R⁶ is C₁ -C₅ -alkyl or C₁ -C₅ -alkoxy, R⁷ is C₁ -C₅ -alkyl, unsubstituted or halogen-substituted benzyl or halogen, m is from 0 to 2, R⁸ is C₁ -C₅ -alkyl, C₃ -C₆ -cycloalkyl, benzyl or phenyl, r⁹ is hydrogen or C₁ -C₅ -alkyl, R¹⁰ is C₁ -C₅ -alkyl or C₁ -C₆ -cycloalkyl, R¹¹ is C₁ -C₅ -alkyl, R¹² is hydrogen, C₁ -C₅ -alkyl or C₃ -C₆ -cycloalkyl, R¹³ is C₁ -C₅ -alkyl or halogen, p is form 0 to 2, R¹⁴ is C₁ -C₅ -alkyl, q is 0 or 1, R¹⁵ and R¹⁶ are each hydrogen, C₁ -C₅ -alkyl or benzyl, R¹⁷ is hydrogen or C₁ -C₅ -alkyl and R¹⁸ is C₁ -C₅ -alkyl, with the proviso that R⁵ is not phenyl when X is oxygen, R¹ is methyl and R² to R⁴ are each hydrogen.

Halogen is preferably chlorine or bromine.

The compounds of the general formula I can be prepared, for example, by reacting a hydroxycoumarin of the formula II ##STR5## where R¹, R², R³ and n have the abovementioned meanings, in a conventional manner with a compound of the formula III ##STR6## where R⁴ and Het are as defined at the outset and Y is a nucleofugic leaving group, such as chlorine, bromine or R⁵ SO₂ O. In this formula, R⁶ is lower alkyl or is phenyl which is unsubstituted or substituted by C₁ -C₃ -alkyl or halogen. The reaction can be carried out, for example as described in Houben-Weyl, Georg Thieme-Verlag, Stuttgart 1965, Vol. 6/3, page 54 et seq., by heating the two components, preferably in the presence of an inert solvent, such as benzene, toluene, methylene chloride, acetone, a lower alcohol, dimethylformamide or water. The reaction temperatures are advantageously from room temperature to the boiling point of the solvent used. The acid liberated is in general trapped by adding a base, such as alkali metal or alkaline earth metal hydroxide or carbonate or an amine, such as pyridine or triethylamine. Instead of the hydroxycoumarins of the formula II, it is also possible to react their alkali metal salts with the compounds of the formula III, preferably under anhydrous conditions in an aprotic solvent, such as ether, tetrahydrofuran, dimethylformamide, dimethoxyethane or dimethyl sulfoxide. The bases used in these cases are alkali metal hydrides or alkali metal alcoholates. Isolation and purification of the products are carried out by conventional methods, for example by recrystallization from a solvent, by column chromatography or if necessary by conversion into an acid addition compound where Het is basic.

The hydroxycoumarins II can be prepared by known methods, as described in, for example, Elderfield R.C., Heterocyclic Compounds, John Wiley Publishers, New York 1951, Vol. 2, page 174 et seq., for example by condensation of a dihydroxybenzene of the formula IV ##STR7## where R³ and n have the abovementioned meanings, with a β-ketocarboxylic ester of the formula V ##STR8## where R¹ and R² have the abovementioned meanings, in the presence of a condensing agent, such as sulfuric acid, phosphoric pentoxide or aluminum chloride.

The heterocyclic derivatives of the general formula III are either known and some of them are commercially available, or they can be prepared by generally known chemical processes. Methods for synthesizing thiophene derivatives are described in, for example, Comprehensive Heterocyclic Chemistry, R. Katritzky and W. Rees, Vol. 4, page 863 et seq., Pergamon Press 1984; furan derivatives in, for example, AU 579 693, U.S. Ser. No. 06/940649 or Advances in Heterocyclic Chemistry, 30 (1982), 167 et seq.; thiazole derivatives, oxazole derivatives, isothiazole derivatives, thiadiazole derivatives and oxadiazole derivatives in, for example, Comprehensive Heterocyclic Chemistry, P. Katritzky and W. Rees, Vol. 6, pages 166, 177, 235, 386 and 425 et seq., Pergamon Press, 1984; imidazole derivatives in, for example, Advances in heterocyclic Chemistry, 27 (1980), 242 et seq.; pyrazole derivatives in, for example, Heteroaromatic Nitrogen Compounds, The Azoles, page 31 et seq., Cambridge University Press, 1976; thiazole derivatives in, for example, Comprehensive Heterocyclic Chemistry, R. Katritzky and W. Rees, Vol. 5, page 733 et seq., Pergamon Press, 1984, and isoxazole derivatives in, for example, GB 1 560 711 and DE-A-2 754 832.

If the compounds of the general formula I are basic, they can be converted into the acid addition salts of a physiologically tolerated acid. Examples of conventional physiologically tolerated organic or inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Further acids are described in Fortschritte der Arzneimittelforschung, Vol. 10, page 224 et seq., Birhauser Verlag, Basle and Stuttgart, 1966.

The acid addition salts are, as a rule, obtained in a conventional manner by mixing the free base or a solution thereof with the corresponding acid or a solution thereof in an organic solvent, for example a lower alcohol, such as methanol ethanol or propanol, or an ether, such as diethyl or methyl tert-butyl ether. To improve deposition of crystals, it is also possible to use a mixture of the stated solvents. If necessary, pharmaceutically tolerated aqueous solutions of acid addition compounds of the novel compounds I can also be prepared by dissolving the free bases in an aqueous acid solution.

The MAO-inhibiting activity of the novel compounds can be determined using standard methods. For example, the determination of monoaminooxidases A and B were determined in dilute rat brain homogenate to which 1. different concentrations of the test substances and 2. ¹⁴ C-phenylethylamine or ¹⁴ C-tryptamine in a concentration of 0.4 μmol/l had been added. The mixture was incubated for 20 minutes at 37° C.

The reaction was then stopped by means of 0.1 normal HCl and the reaction products were determined, after extraction, in a toluene scintillator (PPO+POPOP in toluene). The blank value was determined in similar mixtures with an incubation time of t=0 min.

From the inhibitory values determined at the various inhibitor concentrations against a control, the mean inhibitory concentration (IC50) was calculated by linear regression following logit-log transformation.

The activity of some novel compounds determined in this manner is shown in the Table below:

    ______________________________________                                                  IC50 [μmol/l]                                                                             MAO A                                                   Ex.        MAO A     MAO B     MAO B                                           ______________________________________                                         1            5.6     0.015     370                                             2            3.6     0.003     1200                                            3            1.5     0.0021    710                                             4          ˜10 0.0017    ˜5900                                     6          ˜10 0.0046    ˜2200                                     7          ˜10 0.011     ˜900                                      10         >10       0.0022    >4500                                           13         >10       0.015     >667                                            21         ˜10 0.0077    ˜1300                                     22         >10       0.0016    >6250                                           24         ˜10 0.003     ˜3300                                     25         >10       0.017     >590                                            26         >10       0.0013    >7700                                           29         >10       0.0022    >4500                                           30         >10       0.0057    >1700                                           32         >10       0.0071    >1400                                           33         ˜6  0.00073   ˜8200                                     34         ˜10 0.0022    ˜4500                                     35         >10       0.00092   >11000                                          42           0.35    0.00051   680                                             44         ˜7  0.0012    ˜5800                                     45           0.23    0.00051   450                                             50         ˜4  0.0043    ˜930                                      51         >10       0.0008    >12500                                          54         >10       0.0015    >6700                                           55         >10       0.01      >1000                                           58         ˜7  0.00084   ˜8300                                     61         >10       0.0019    >1100                                           62         >10       0.0075    >1300                                           67         >10       0.0011    >9100                                           68         >10       0.00077   >13000                                          70         >10       0.013     >770                                            72         ˜10 0.0049    ˜2000                                     73         >10       0.014     >700                                            74           3.2     0.0055    580                                             75         ˜10 0.0014    ˜7000                                     78         >10       0.0013    >7700                                           79           2.9     0.0012    2400                                            80         ˜10 0.0014    ˜7100                                     84         >10       0.0091    >1100                                           85         >10       0.0069    >1700                                           87         >10       0.014     >700                                            92         >10       ˜0.01                                                                              >1000                                           94         ˜10 0.0012    ˜8300                                     96         ˜20 0.00061   ˜32000                                    97         ˜5  0.0036    ˜1400                                     98         >10       0.00092   >11000                                          99         >10       0.0082    >1200                                           100        >10       0.00074   >13000                                          101        >10       0.001     >10000                                          103        >10       0.0018    >5500                                           108        ˜10 0.0009    ˜11000                                    109        >10       0.00088   >11000                                          Deprenyl     2.0     0.0078    256                                             Ro 19-6327 >10       0.022     >450                                            ______________________________________                                    

The novel compounds can be administered in a conventional manner, orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally).

The dose depends on the age, condition and weight of the patient and on the route of administration. As a rule, the daily dose of active compound is from about 10 to 500 mg per patient per day in the case of oral administration and from about 1 to 50 mg per patient per day in the case of parenteral administration.

The novel compounds can be used in the conventional solid or liquid pharmaceutical forms, for example as tablets, film tablets, capsules, powders, granules, coated tablets, suppositories, solutions or sprays. These are prepared in a conventional manner and to do so the active ingredients are mixed with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellants (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms thus obtained normally contain the active compound in a concentration of from 1 to 99% by weight.

EXAMPLE 1 3,4-Dimethyl-7-(2-methyl-1,3,4-oxadiazol-5-yl)-methoxycoumarin

5.0 g of 7-hydroxy-3,4-dimethylcoumarin in 20 ml of diemthylformamide were added dropwise to a suspension of 0.9 g of NaH (80%) in 50 ml of dimethylformamide at room temperature. After 45 minutes, 3.5 g of 2-chloromethyl-5-methyl-1,3,4-oxadiazole, dissolved in 20 ml of dimethylformamide, were added and the mixture was stirred overnight at room temperature. The reaction solution was hydrolyzed with ice water, and the precipitated solid was filtered off under suction and recrystallized from methanol.

Yield: 4.28 g (57%), mp. 159° C.

C₁₅ H₁₄ N₂ O₄ (286): Calculated: 62.93, C; 4.93, H; 9.78, N; 22.35, O. Found: 63.0, C; 4.9, H; 9.7, N; 22.2, O.

EXAMPLE 2 3,4-Dimethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

A mixture of 5.0 g of 7-hydroxy-3,4-dimethylcoumarin, 3.9 g of 2-chloromethyl-5-methyl-1,3,4-thiadiazole, 3.5 g of K₂ CO₃ and 100 ml of acetone was refluxed for 20 hours and evaporated down, and the residue was partitioned in H₂ O/methylene chloride. After the undissolved constituents had been separated off, the organic phase was washed once with 1 N NaOH and then with H₂ O, dried over Na₂ SO₄ and evaporated down, and the residue was recrystallized from methanol and dried.

Yield: 5.8 g (74%), mp. 150° C.

C₁₅ H₁₄ N₂ O₃ S (302): Calculated: 59.59, C; 4.67, H; 9.27, N; 15.87, O; 10.60, S. Found: 59.4, C; 4.5, H; 9.4, N; 16.0, O; 10.6, S.

The following were prepared similarly to Example 2:

EXAMPLE 3 3,4-Dimethyl-7-(3-methylisoxazol-5-yl)-methoxycoumarin

Yield: 43%; mp. 148°-150° C. (ethanol)

C₁₆ H₁₅ NO₄ (285): Calculated: 67.36, C; 5.30, H; 4.91, N; 22.43, O. Found: 67.2, C; 5.4, H; 5.1, N; 22.3, O.

The following were prepared similarly to Example 1:

EXAMPLE 4 3,4-Dimethyl-7-(3-n-propylisoxazol-5-yl)-methoxycoumarin

Yield: 50%; mp. 94° C. (methanol)

C₁₈ H₁₉ NO₄ (313): Calculated: 68.99, C; 6.11, H; 4.47, N; 20.42, O. Found: 68.7, C; 6.2, H; 4.4, N; 20.2, O.

EXAMPLE 5 3,4-Dimethyl-7-(4-pyridinyl)-methoxycoumarin

Yield: 52%; mp. 171° C. (methanol)

C₁₇ H₁₅ NO₃ (281); Calculated: 72.58, C; 5.37, H; 4.98, N; 17.06, O. Found: 72.3, C; 5.5, H; 4.8, N; 16.9, O.

EXAMPLE 6 7-(3-Methoxymethylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 70%; mp. 133° C. (methanol)

C₁₇ H₁₇ NO₅ (315). Calculated: 64.75, C; 5.43, H; 4.44, N; 25.37, O. Found: 64.7, C; 5.55, H; 4.2, N; 25.0, O.

EXAMPLE 7 7-(2-Ethyl-1,3,4-oxadiazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 54%; mp. 118° C. (methanol)

C₁₆ H₁₆ N₂ O₄ (300): Calculated: 63.99, C; 5.37, H; 9.33, N; 21.31, O. Found: 63.7, C; 5.8, H; 9.3, N; 21.3, O.

EXAMPLE 8 3,4-Dimethyl-7-(2-pyridinyl)-methoxycoumarin

Yield: 76% mp. 156° C. (methanol)

C₁₇ H₁₅ NO₃ (281): Calculated: 72.58, C; 5.37, H; 4.98, N; 17.06, O. Found: 72.4, C; 5.5, H; 5.0, N; 16.9, O.

EXAMPLE 9 3,4-Dimethyl-7-(3-pyridinyl)-methoxycoumarin

Yield: 64%; mp. 154° C. (methanol)

C₁₇ H₁₅ NO₃ (281): Calculated: 72.58, C; 5.37, H; 4.98, N; 17.06, O. Found: 72.4, C; 5.6, H; 4.9, N; 16.9, O.

EXAMPLE 10 3.6-Dichloro-4-methyl-7-(2-cyclopropylthiazol-4-yl)-methoxycoumarin

The procedure and working up were carried out similarly to Example 2. In addition, 0.1% of 18-crown-6 was added to the reaction mixture.

Yield: 26% mp. 182°-184° C. (methanol)

C₁₇ H₁₃ Cl₂ NO₃ S (382): Calculated: 53.41, C; 3.43, H; 18.55, Cl; 3.66, N; 12.56, O; 8.39, S. Found: 53.0, C; 3.5, H; 19.0, Cl; 3.6, N; 12.4, O; 8.1, S.

EXAMPLE 11 7-(2-Chlorothiophen-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 69%; mp. 152°-154° C. (methanol)

C₁₆ H₁₃ ClO₃ S (321): Calculated: 59.91 C; 4.08 H; 11.05 N; 14.96 O; 10.00 S. Found: 59.4 C; 4.2 H; 11.0 N; 14.8 O; 10.0 S.

EXAMPLE 12 7-(2-Methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 64%; mp. 155° C. (methanol)

C₁₃ H₁₀ N₂ O₃ S (274): Calculated: 56.92, C; 3.67, H; 10.21, N; 17.50, O; 11.69, S. Found: 56.6, C; 3.6 H; 10.3, N; 17.4, O; 11.6 S.

EXAMPLE 13 3-Methyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 59%; mp. 177° C. (methanol)

C₁₄ H₁₂ N₂ O₃ S (288): Calculated: 58.32, C; 4.19, H; 9.72, N; 16.65, O; 11.12, S. Found: 58.1, C; 4.3, H; 9.6, N; 16.7, O; 11.3, S.

EXAMPLE 14 4-Methyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 56%; mp. 143°-144° C. (methanol)

C₁₄ H₁₂ N₂ O₃ S (288): Calculated: 58.32, C; 4.20, H; 9.72, N; 16.65, O; 11.12, S. Found: 58.4, C; 4.4, H, 9.6, N; 16.5, O; 10.9, S.

EXAMPLE 15 7-(Benzimidazol-2-yl)-methoxy-3,4-dimethylcoumarin

Yield: 20%; mp. 271°-274° C. (methanol)

C₁₉ H₁₆ N₂ O₃ (320): Calculated: 71.24, C; 5.03, H; 8.74, N; 14.98, O. Found: 70.8, C; 5.3, H; 8.6, N; 15.2, O.

EXAMPLE 16 7-(Quinolin-2-yl)-methoxy-3,4-dimethylcoumarin

Yield: 66%; mp. 189°-190° C. (methanol)

C₂₁ H₁₇ NO₃ (331): Calculated: 76.12, C; 5.17, H; 4.23, N; 14.48, O. Found: 76.1, C; 5.2, H; 4.2, N; 14.3, O.

EXAMPLE 17 3,4-Dimethyl-7-(1-methylpiperidin-3-yl)-methoxycoumarin

The reaction mixture was stirred for 12 hours at 120° C. The preparation and working up were carried out as described under Example 1.

Yield: 55%; mp. 126°-128° C. (methanol)

C₁₈ H₂₃ NO₃ (301): Calculated: 71.73, C; 7.69, H; 4.65, N; 15.93, O. Found: 71.8, C; 7.8, H; 4.5, N; 15.8, O.

EXAMPLE 18 7-(Tetrahydrofuran-2-yl)-methoxy-3,4-dimethylcoumarin

The reaction mixture was stirred for 12 hours at 120° C. The preparation and working up were carried out as described under Example 1. Yield: 55%; mp. 151°-153° C. (methanol)

C₁₆ H₁₈ O₄ (274): Calculated: 70.06, C; 6.61, H; 23.33, O. Found: 70.1, C; 6.7, H; 23.2, O.

EXAMPLE 19 7-[3-(3,4-Dichlorophenyl)-isoxazol-5-yl]-methoxy-3,4-dimethylcoumarin

Yield: 56%; mp. 225° C.

C₂₁ H₁₅ Cl₂ NO₄ (416): Calculated: 60.59 C; 3.63 H; 17.03, Cl; 3.36, N; 15.37, O. Found: 60.2, C; 3.8, H; 17.2, Cl; 3.3, N; 15.4, O.

EXAMPLE 20 3,4-Dimethyl-7-[3-(3-nitrophenyl)-isoxazol-5-yl]-methoxycoumarin

Yield: 20%; mp. 212°-219° C. (decomposition)

C₂₁ H₁₆ N₂ O₂ (392): Calculated: 64.28, C; 4.11, H; 7.14, N, 24.47, O. Found: 63.8, C; 4.5, H; 6.9, N, 24.0, O.

EXAMPLE 21 7-(Benzodioxan-2-yl)-methoxy-3,4-dimethylcoumarin

The reaction mixture was stirred for 12 hours at 120° C. The preparation and working up were carried out as described under Example 1.

Yield: 53%; mp. 145° C. (ethanol)

C₂₀ H₁₈ O₅ (338): Calculated: 71.0, C; 5.36, H; 23.64, O. Found: 70.8, C; 5.4, H; 23.4, O.

EXAMPLE 22 7-(2-Benzylfuran-4-yl)-methoxy-3,4-dimethylcoumarin

Yield: 68%; mp. 113° C. (methanol)

C₂₃ H₂₀ O₄ (360): Calculated: 76.65, C; 5.59, H; 17.76, O.

Found: 76.4, C; 5.6, H; 17.7, O.

EXAMPLE 23 7-(2-Methyl-1,3,4-thiadiazol-5-yl)-methoxy-4-phenylcoumarin

The reaction mixture was stirred for 3 hours at 100° C. and overnight at room temperature. The preparation and working up were carried out as described under Example 1.

Yield: 80%; mp. 166°-167° C. (methanol)

C₁₉ H₁₄ N₂ O₃ S (350) Calculated: 65.13, C; 4.03, H, 7.99, N; 13.70, O; 9.15, S. Found: 65.3, C; 4.1, H; 8.0, N; 13.9, O; 9.1, S.

EXAMPLE 24 3,4-Dimethyl-7-(2-methylthiazol-4-yl)-methoxycoumarin

Yield: 69%; mp. 149°-150° C. (methanol)

C₁₆ H₁₅ NO₃ S (301): Calculated: 63.77, C; 5.02, H; 4.65, N; 15.93, O; 10.64, S. Found: 63.5, C; 5.1, H; 4.6, N; 16.1, O; 10.4, S.

EXAMPLE 25 7-[2-(3-Chlorobenzyl)-furan-4-yl]-methoxy-3,4-dimethylcoumarin

Yield: 45%; mp. 115° C. (methanol)

C₂₃ H₁₉ ClO₄ (395): Calculated: 69.96, C; 4.85, H; 8.98, Cl; 16.21, O. Found: 69.9, C; 5.1, H; 8.8, Cl; 16.5, O.

EXAMPLE 26 7-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 82%; mp. 142° C. (methanol)

C₁₇ H₁₈ N₂ O₄ (314): Calculated: 64.96, C; 5.77, H; 8.91, N; 20.36, O. Found: 64.8, C; 5.9, H; 8.9, N; 20.4, O.

EXAMPLE 27 3,4-Dimethyl-7-[3-(tetrahydropyran-4-yl)-isoxazol-5-yl]-methoxycoumarin

Yield: 77%; mp. 151° C. (methanol)

C₂₀ H₂₁ NO₅ (355): Calculated: 67.59, C; 5.96, H; 3.94, N; 22.51, O. Found: 67.5, C; 5.9, H; 4.0, N; 22.5, O.

EXAMPLE 28 7-(4,5-Dihydro-3-propylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

The reaction mixture was stirred for 8 hours at 100° C. The preparation and working up were carried out as described under Example 1.

Yield: 60%; mp. 147° C. (methanol)

C₁₈ H₂₁ NO₄ (315): Calculated: 68.55, C; 6.71, H; 4.44, N; 20.29, O. Found: 68.3, C; 6.7, H; 4.3, N; 20.0, O.

EXAMPLE 29 7-(5-Isopropyl-1-methylpyrazol-3-yl)-methoxy-3,4-dimethylcoumarin

Yield: 43%; mp. 113° C. (methanol)

C₁₉ H₂₂ N₂ O₃ (326): Calculated: 69.92, C; 6.79, H; 8.58, N; 14.71, O. Found: 69.5, C; 6.9, H; 8.4, N; 14.6, O.

EXAMPLE 30 3-Chloro-4-methyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 62%; mp. 176°-177° C. (methanol)

C₁₄ H₁₁ ClN₂ O₃ S (323): Calculated: 52.10, C; 3.44, H; 10.98, Cl; 8.68, N; 14.87, O; 9.93, S. Found: 52.2, C; 3.6, H; 10.8, Cl; 8.7, N; 15.2, O; 9.2, S.

EXAMPLE 31 3-Ethyl-4-methyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 78%; mp. 167° C. (methanol)

C₁₆ H₁₆ N₂ O₃ S (316) Calculated: 60.74, C; 5.10, H; 8.85, N; 15.17, O; 10.13, S. Found: 60.6, C; 5.2, H; 9.0, N; 15.1, O; 10.1, S.

EXAMPLE 32 3,4-Tetramethylen-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 81%; mp. 172°-174° C. (methanol)

C₁₇ H₁₆ N₂ O₃ S (338): Calculated: 62.18, C; 4.91, H; 8.53, N; 14.62, O; 9.76, S. Found: 61.8, C; 5.1, H; 8.7, N; 14.8, O; 9.7, S.

EXAMPLE 33 7-(3-Isopropylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 62%; mp. 105° C. (methanol) C₁₈ H₁₉ NO₄ (313): Calculated: 69.00, C; 6.11, H; 4.47, N; 20.42, O. Found: 68.8, C; 6.3, H; 4.4, N; 20.4, O.

EXAMPLE 34 7-(3-Isobutylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 79%; mp. 86° C. (methanol)

C₁₉ H₂₁ NO₄ (327): Calculated: 69.71, C; 6.47, H; 4.28, N; 19.55, O. Found: 69.7, C; 6.7, H; 4.3, N; 19.5, O.

EXAMPLE 35 7-(3-tert-Butylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 58%; mp. 121° C. (methanol)

C₁₉ H₂₁ NO₄ (327): Calculated: 69.71, C; 6.47, H; 4.28, N; 19.55, O. Found: 69.7, C; 6.7, H; 4.3, N; 19.4, O.

EXAMPLE 36 7-(3-Ethoxycarbonylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 71%; mp. 202° C. (methylene chloride/ethyl acetate)

C₁₈ H₁₇ NO₆ (343) Calculated: 62.97, C; 4.99, H; 4.08, N; 27.96, O. Found: 62.7, C; 5.1, H; 4.0, N; 27.8, O.

EXAMPLE 37 7-(4,5-Dichloroimidazol-1-yl)-methoxy-3,4-dimethylcoumarin

Yield: 84%; mp. 235° C. (methylene chloride/ethyl acetate)

C₁₅ H₁₂ Cl₂ N₂ O₃ (339): Calculated: 53.12, C; 3.57, H; 20.91, Cl; 8.26, N; 14.15, O. Found: 52.2, C; 3.6, H; 20.6, Cl; 8.0, N; 14.2, O.

EXAMPLE 38 3,4-Dimethyl-7-(1,2,4-triazol-1-yl)-methoxycoumarin

Yield: 73%; mp. 223°-225° C. (methanol) C₁₄ H₁₃ N₂ O₃ (271): Calculated: 61.99, C; 4.83, H; 15.49, N; 17.69, O. Found: 61.8, C; 5.0, H; 15.6, N; 17.5, O.

EXAMPLE 39 3,4-Dimethyl-7-(4,5-dimethylimidazol-1-yl)-methoxycoumarin

Yield: 37%; mp. 196°-198° C. (ethyl acetate)

C₁₇ H₁₈ N₂ O₃ (298): Calculated: 68.44, C; 6.08, H; 9.39, N; 16.09, O. Found: 68.1, C; 6.2, H; 9.4, N; 16.0, O.

EXAMPLE 40 3,4-Dimethyl-7-(thiophen-2-yl)-methoxycoumarin

Yield: 43%; mp. 169°-172° C. (methanol) C₁₆ H₁₄ O₃ S (286): Calculated: 67.11, C; 4.93, H; 16.76, O; 11.20, S. Found: 67.0, C; 5.0, H; 16.8, O; 11.2, S.

EXAMPLE 41 3,4-Dimethyl-7-(thiophen-3-yl)-methoxycoumarin

Yield: 41%; mp. 158°-160° C. (methanol)

C₁₆ H₁₄ O₃ S (286): Calculated: 67.11, C; 4.93, H; 16.76, O; 11.20, S. Found: 66.9, C; 5.1, H; 16.8, O; 11.1, S.

EXAMPLE 42 3,4-Dimethyl-7-(2-methylthiophen-5-yl)-methoxycoumarin

Yield: 66%; mp. 123°-126° C. (methanol)

C₁₇ H₁₆ O₃ S (300): Calculated: 67.98, C; 5.37, H; 15.98, O; 10.67, S. Found: 67.8, C; 5.5, H; 15.9, O; 10.7, S.

EXAMPLE 43 7-(2-Chlorothiophen-4-yl)-methoxy-3,4-dimethylcoumarin

Yield: 53%; mp. 137°-139° C. (methanol)

C₁₆ H₁₃ ClO₃ S (321): Calculated: 59.91, C; 4.08, H; 11.05, Cl; 14.96, O; 10.0, S. Found: 59.6, C; 4.1, H; 11.0, Cl; 15.1, O; 9.9, S.

EXAMPLE 44 3,4-Dimethyl-7-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-methoxycoumarin

Yield: 41%; mp. 128°-131° C. (methanol)

C₁₇ H₁₆ N₂ O₄ (312): Calculated: 65.38, C; 5.16, H; 8.97, N; 20.49, O. Found: 65.1, C; 5.2, H; 9.0, N; 20.6, O.

EXAMPLE 45 3,4-Dimethyl-7-(3-methylthiophen-2-yl)-methoxycoumarin

Yield: 52%; mp. 147° C. (methanol)

C₁₇ H₁₆ O₃ S (300) Calculated: 67.98, C; 5.37, H; 15.98, O; 10.67, S.

Found: 68.0, C; 5.4, H; 15.9, O; 10.7, S.

EXAMPLE 46 7-(2-Bromothiophen-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 65%; mp. 140°-143° C. (ethyl acetate)

C₁₆ H₁₃ BrO₃ S (365) Calculated: 52.62, C; 3.59, H; 21.88, Br; 13.14, O; 8.78, S. Found: 52.7, C; 3.9, H; 21.7, Br; 13.3, O; 8.8, S.

EXAMPLE 47 7-(2-Bromothiophen-4-yl)-methoxy-3,4-dimethylcoumarin

Yield: 67%; mp. 104° C. (ethanol)

C₁₆ H₁₃ BrO₃ S (365): Calculated: 52.62, C; 3.59, H; 21.88, Br; 13.14, O; 8.78, S. Found: 52.7, C; 3.7, H; 21.4, Br; 13.4, O; 8.8, S.

EXAMPLE 48 7-(4-Bromothiophen-2-yl)-methoxy-3,4-dimethylcoumarin

Yield: 53%; mp. 131°-134° C. (methanol)

C₁₆ H₁₃ BrO₃ S (365): Calculated: 52.62, C; 3.59, H; 21.88, Br; 13.14, O; 8.78, S. Found: 52.3, C; 3.7, H; 21.5, Br; 13.3, O; 8.7, S.

EXAMPLE 49 7-(2,3-Dibromothiophen-4-yl)-methoxy-3,4-dimethylcoumarin

Yield: 57%; mp. 194°-196° C. (methanol)

C₁₆ H₁₂ Br₂ O₃ S (444): Calculated: 43.27, C; 2.72, H; 35.98, Br; 10.81, O; 7.22, S. Found: 43.2, C; 2.7, H; 35.9, Br; 11.1, O; 7.1, S.

EXAMPLE 50 3,4-Dimethyl-7-(3-methyl-1,2,4-oxadiazol-5-yl)-methoxycoumarin

Yield: 63%; mp. 172°-174° C. (methanol)

C₁₅ H₁₄ N₂ P₄ (286) Calculated: 62.93, C; 4.89, H; 9.79, N; 22.37, O. Found: 62.6, C; 5.0, H; 9.8, N; 22.9, O.

EXAMPLE 51 7-(3-Cyclopropylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 36% mp. 158°-160° C. (methanol)

C₁₈ H₁₇ NO₄ (311): Calculated: 69.44, C; 5.50, H; 4.50, N; 20.56, O. Found: 69.0, C; 5.6, H; 4.5, N; 21.2, O.

EXAMPLE 52 3,4-Dimethyl-7-(3-methylisothiazol-4-yl)-methoxycoumarin

Yield: 28%; mp. 163°-165° C. (methanol)

C₁₆ H₁₅ NO₃ S (301): Calculated: 63.77, C; 5.02, H; 4.65, N; 15.93, O; 10.64, S. Found: 63.9, C; 5.1, H; 4.7, N; 15.5, O; 10.5, S.

EXAMPLE 53 3,4-Dimethyl-7-(1,2,3-thiadiazol-4-yl)-methoxycoumarin

Yield: 39%; mp. 171°-173° C. (methanol)

C₁₄ H₁₂ N₂ O₃ S (288): Calculated: 56.51, C; 4.38, H; 10.14, N; 17.37, O; 11.6, S. Found: 56.9, C; 4.1, H; 9.6, N; 17.7, O; 11.8, S.

EXAMPLE 54 3-Chloro-7-(5-isopropyl-1-methylpyrazol-3-yl)-methoxy-4-methylcoumarin

The reaction was carried out as described under Example 1. After the hydrolysis, extraction was carried out with methylene chloride, the organic phase was washed with H₂ O, dried over Na₂ SO₄ and evaporated down and the residue was recrystallized from methanol.

Yield: 33% mp. 162°-165° C.

C₁₈ H₁₉ ClN₂ O₃ (346.5): Calculated: 62.34, C; 5.52, H; 8.08, N; 13.84, O; 10.22, S.

Found: 62.3, C; 5.8, H; 8.1, N; 13.7, O; 9.7, S.

EXAMPLE 55 7-(5-Isopropyl-1-methylpyrazol-3-yl)-methoxy-3,4-tetramethlenecoumarin

Yield: 29%; mp. 138°-140° C. (methanol)

C₂₁ H₂₄ N₂ O₃ (352): Calculated: 71.57, C; 6.86, H; 7.95, N; 13.62, O. Found: 7.10, C; 6.9, H; 8.0, N; 14.1, O.

EXAMPLE 56 4-Ethyl-3-methyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 24%; mp. 135°-138° C. (methanol)

C₁₆ H₁₆ N₂ O₃ S (316): Calculated: 60.74, C; 5.10, H; 8.85, N; 15.17, O; 10.13, S. Found: 61.0, C; 5.5, H; 8.5, N; 15.0, O; 9.8, S.

EXAMPLE 57 3,4-Dimethyl-7-(4-methyl-1,2,3-thiadiazol-5-yl)-methoxycoumarin

Yield: 29%; mp. 204°-206° C. (methanol)

C₁₅ H₁₄ N₂ O₃ S (302): Calculated: 59.60, C; 4.63, H; 9.27, N; 15.89, O; 10.59, S. Found: 59.3, C; 4.8, H; 9.3, N; 15.9, O; 10.7, S.

EXAMPLE 58 7-(5-Cyclopropylisoxazol-3-yl)-methoxy-3,4-dimethylcoumarin

Yield: 67%; mp. 107°-109° C. (methanol)

C₁₈ H₁₇ NO₄ (311): Calculated: 69.44, C; 5.50, H; 4.50, N; 20.56, O. Found: 69.1, C; 5.8, H; 4.3, N; 20.4, O.

EXAMPLE 59 7-(3-Trifluoromethylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 47%; mp. 180°-182° C. (methanol)

C₁₆ H₁₂ F₃ NO₄ (339): Calculated: 56.64, C; 3.57, H; 16.80, F; 4.13, N; 18.86, O. Found: 56.6, C; 3.7, H; 16.8, F; 4.0, N; 18.9, O.

EXAMPLE 60 3,4-Dimethyl-7-(1-methylimidazol-2-yl)-methoxycoumarin

The procedure and working up were carried out as described under Example 54.

Yield: 28%; mp. 182°-185° C.

C₁₆ H₁₆ N₂ O₃ (284): Calculated: 67.59, C; 5.67, H; 9.85, N; 16.88, O. Found: 67.2, C; 6.0, H; 9.7, N; 16.5, O.

EXAMPLE 61 7-(5-Cyclopropyl-1-methylpyrozol-3-yl)-methoxy-3,4-dimethylcoumarin

Yield: 51%; mp. 124°-127° C. (methanol)

C₁₉ H₂₀ N₂ O₃ (324): Calculated: 70.35, C; 6.21, H; 8.64, N; 14.80, O. Found: 70.1, C; 6.4, H; 8.7, N; 14.6, O.

EXAMPLE 62 7-(2-Ethoxy-1,3,4-thiadiazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 37%; mp. 174°-176° C. (methanol)

C₁₆ H₁₆ N₂ O₄ S (332): Calculated 57.82, C; 4.85, H; 8.43, N; 19.25, O; 9.65, S. Found: 58.3, C; 5.3, H; 8.1, N; 18.9, O; 9.4 S.

EXAMPLE 63 3,4-Dimethyl-7-(2-phenylthiazol-4-yl)-methoxycoumarin

The procedure and working up were carried out as described under Example 54.

Yield: 39%; mp. 152°-154° C. (methanol)

C₂₁ H₁₇ NO₃ S (363): Calculated: 69.40, C; 4.71, H; 3.85, N; 13.21, O; 8.82, S. Found: 69.1, C; 4.9, H; 3.7, N; 13.1, O; 9.0, S.

EXAMPLE 64 4-Ethyl-7-(5-isopropyl-1-methylpyrazol-3-yl)-methoxy-3-methylcoumarin

The procedure and working up were carried out as described under Example 54.

Yield: 33%; mp. 101°-103° C.

C₂₀ H₂₄ N₂ O₃ (340): Calculated: 70.57, C; 7.11, H; 8.23, N; 14.10, O. Found: 70.2, C; 7.5, H; 8.3, N; 13.7, O.

EXAMPLE 65 6-Chloro-3,4-dimethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 37%; mp. 209°-210° C. (methanol)

C₁₅ H₁₃ ClN₂ O₃ S (336.5): Calculated: 53.49, C; 3.89, H; 10.53, Cl; 8.32, N; 14.25, O; 9.52, S. Found: 53.3, C; 3.9, H; 10.5, Cl; 8.2, N; 14.1, O; 9.6, S.

EXAMPLE 66 3,4-Dimethyl-7-(4-methylisothiazol-5-yl)-methoxycoumarin

Yield: 25%; mp. 180° C. (methanol)

C₁₆ H₁₅ NO₃ S (301): Calculated: 63.56, C; 5.33, H; 4.64, N; 15.87, O; 10.6, S. Found: 63.5, C; 5.3, H; 4.8, N; 15.3, O; 10.9, S.

EXAMPLE 67 6-Bromo-3,4-dimethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 36%; mp. 205° C. (methanol)

C₁₅ H₁₃ BrN₂ O₃ S (381): Calculated: 47.26, C; 3.44, H; 20.96, Br; 7.35, N; 12.59, O; 8.41, S. Found: 47.1, C; 3.5, H; 20.8, Br; 7.4, N; 12.7, O; 8.5, S.

EXAMPLE 68 7-(3-Cyclobutylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

The procedure and working up were carried out as described under Example 54.

Yield: 26%; mp. 100°-101° C. (methanol)

C₁₉ H₁₉ NO₄ (325): Calculated: 70.15, C; 5.84, H; 4.3, N; 19.7, O. Found: 69.9, C; 5.9, H; 4.6, N; 19.5, O.

EXAMPLE 69 7-(1-Benzyl-1,2,4-triazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 49% mp. 151°-152° C. (methanol)

C₂₁ H₁₉ N₃ O₃ (361): Calculated: 69.79, C; 5.30, H; 11.63, N; 13.28, O. Found: 69.3, C; 5.5, H; 11.8, N; 13.6, O.

EXAMPLE 70 7-(1-Isopropyl-1,2,4-trizol-5-yl)-methoxy-3,4-dimethylcoumarin hydrochloride

The procedure was carried out as described under Example 1. After the hydrolysis, extraction was effected with methylene chloride and the organic phase was evaporated down and the residue was purified by column chromatography (silica gel; 20:1 CH₂ Cl₂ /CH₃ OH). The free base was dissolved in CH₂ Cl₂ and HCl in ether was added. The precipitate formed was filtered off under suction, washed with a little ether and dried.

Yield: 32%; mp. 179°-181° C.

C₁₇ H₂₀ ClN₃ O₃ (350): Calculated: 58.37, C; 5.76, H; 10.13, Cl; 12.01, N; 13.71, O. Found: 57.9, C; 5.9, H; 10.0, Cl; 12.1, N; 14.2, O.

EXAMPLE 71 3,4-Dimethyl-7-[1-(1,3-dimethyl-1,2,4-triazol-5-yl)]-ethoxycoumarin

Yield: 32%; mp. 160°-162° C. (methanol)

C₁₇ H₁₉ N₃ O₃ (313): Calculated: 65.16, C; 6.11, H; 13.41, N; 15.32, O. Found: 65.1, C; 6.2, H; 13.3, N; 15.6, O.

EXAMPLE 72 7-(3-Isopropyl-1-methylpyrazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 37%; mp. 125°-126° C. (methanol)

C₁₉ H₂₂ N₂ O₃ (326): Calculated: 69.92, C; 6.79, H; 8.58, N; 14.71, O. Found: 69.3, C; 7.1, H; 9.1, N; 14.3, O.

EXAMPLE 73 3,4-Dimethyl-7-(1,5-dimethylpyrazol-3-yl)-methoxycoumarin

Yield: 23%; mp. 169°-17° C. (methanol)

C₁₇ H₁₈ N₂ O₃ (298): Calculated: 68.44, C; 6.08, H; 9.39, N; 16.09, O. Found: 68.2, C; 6.3, H; 9.1, N; 16.3, O.

EXAMPLE 74 7-(2-Benzylthiazol-4-yl)-methoxy-3,4-dimethylcoumarin

Yield: 21%; mp. 142°-143° C. (methanol)

C₂₂ H₉ NO₃ S (377): Calculated: 70.01, C; 5.07, H; 3.71, N; 12.72, O; 8.49, S. Found: 69.6, C; 5.2, H; 3.7, N; 13.0, O; 8.4, S.

EXAMPLE 75 7-(2-Isopropylthiazol-4-yl)-methoxy-3,4-dimethylcoumarin

Yield: 20%; mp. 103° C. (methanol)

C₁₈ H₁₉ NO₃ S (329) Calculated: 65.63, C; 5.81, H; 4.25, N; 14.57, O; 9.79, S. Found: 65.0, C; 6.0, H; 3.9, N; 15.2, O; 9.2, S.

EXAMPLE 76 3,4,8-Trimethyl-7-(2-methyl-1,3,4-thiaziazol-5-yl)-methoxycoumarin

Yield: 62%; mp. 231°-233° C. (methanol)

C₁₆ H₁₆ N₂ O₃ S (316): Calculated: 60.74, C; 5.10, H; 8.85, N; 15.17, O; 10.13, S. Found: 60.5, C; 5.2, H; 9.0, N; 15.1, O; 10.3, S.

EXAMPLE 77 3,4,5-Trimethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 76%; mp. 201°-203° C. (methanol)

C₁₆ C₁₆ N₂ O₃ S (316) Calculated: 60.74, C; 5.10, H; 8.85, N; 15.17, O; 10.13, S. Found: 60.5, C; 5.2, H; 9.0, N; 15.1, O; 10.1, S.

EXAMPLE 78 7-(3-Cyclopentylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

The procedure was carried out as described under Example 1. After the hydrolysis, the precipitated solid was filtered off under suction and extracted by boiling with 5 times 100 ml of n-heptane. The combined heptane phases were evaporated down and the residue was recrystallized with methanol.

Yield: 15%; mp. 81°-83° C.

C₂₀ H₂₁ NO₄ (339): Calculated: 70.78, C; 6.24, H; 4.13, N; 18.86, O. Found: 70.6, C; 6.2, H; 4.0, N; 18.8, O.

EXAMPLE 79 7-[3-(1-Methoxyethyl)-isoxazol-5-yl]-methoxy-3,4-dimethylcoumarin

The reaction mixture was stirred for 12 hours at 70° C. The preparation and working up were carried out as described under Example 1.

Yield: 37%; mp. 124°-127° C. (methanol)

C₁₈ H₁₉ NO₅ (329): Calculated 65.64, C; 5.81, H; 4.25, N; 24.29, O. Found: 65.4, C; 6.0, H; 4.2, N; 24.7, O.

EXAMPLE 80 7-(2-Cyclopropylthiazol-4-yl)-methoxy-3,4-dimethylcoumarin

The reaction mixture was stirred for 12 hours at 70° C. The preparation and working up were carried out as described under Example 1.

Yield: 51%; mp. 151° C. (methanol)

C₁₈ H₁₇ NO₃ S (327): Calculated: 66.03, C; 5.23, H, 4.28, N; 14.66, O; 9.79, S. Found: 65.7, C; 5.4, H; 4.4, N; 15.0, O; 9.7, S.

EXAMPLE 81 3,4-Dimethyl-7-(1-methylpyrazol-3-yl)-methoxycoumarin

Yield: 47%; mp. 135° C. (methanol)

C₁₆ H₁₆ N₂ O₃ (284) Calculated: 67.59, C; 5.67, H; 9.85, N; 16.88, O. Found: 67.5, C; 5.8, H; 9.8, N; 17.0, O.

EXAMPLE 82 7-(5-Isopropyl-1-methylpyrazol-3-yl)-methoxy-3,4,5-trimethylcoumarin

Yield: 65%; mp. 128° C. (methanol)

C₂₀ H₂₄ N₂ O₃ (340): Calculated: 70.57, C; 7.11, H; 8.23, N; 14.10, O. Found: 70.3, C; 7.1, H; 8.1, N; 14.5, O.

EXAMPLE 83 7-(5-Isopropyl-1-methylpyrazol-3-yl)-methoxy-3,4,8-trimethylcoumarin

Yield: 46%; mp. 146°-148° C. (methanol)

C₂₀ H₂₄ N₂ O₃ (340): Calculated: 70.57, C; 7.11, H; 8.23, N; 14.10, O. Found: 70.3, C; 7.1, H; 8.1, N; 14.5, O.

EXAMPLE 84 6-Ethyl-7-(5-isopropyl-1-methylpyrazol-3-yl)-methoxy-3,4-dimethylcoumarin

Yield: 51%; mp. 136°-137° C. (methanol)

C₂₁ H₂₆ N₂ O₃ (354): Calculated 71.16, C; 7.39, H; 7.90, N; 13.54, O. Found: 71.1, C; 7.5, H; 7.9, N; 13.6, O.

EXAMPLE 85 6-Ethyl-3,4-dimethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 80% mp. 201°-203° C. (methanol)

C₁₇ H₁₈ N₂ O₃ S (330): Calculated: 61.80, C; 5.49, H; 8.48, N; 14.53, O; 9.70, S. Found: 61.7, C; 5.6, H; 8.4, N; 14.6, O; 9.7, S.

EXAMPLE 86 3,4-Dimethyl-7-[3-(pyridine-2-yl)-isoxazol-5-yl]-methoxycoumarin

Yield: 86%; mp. 193° C. (methanol)

C₂₀ H₁₆ N₂ O₄ (348): Calculated: 68.96, C; 4.64, H; 8.04, N; 18.37, O. Found: 68.4, C; 4.6, H; 8.1, N; 17.9, O.

EXAMPLE 87 7-(3-Cyclohexylisoxazol-5-yl)-methoxy-3,4-dimethylcoumarin

The procedure and working up were carried out as described under Example 78.

Yield: 66%; mp. 122° C. (n-heptane)

C₂₁ H₂₃ NO₄ (353): Calculated: 71.73, C; 6.56, H; 3.86, N; 18.11, O. Found: 71.5, C; 6.7, H; 4.0, N; 17.8, O.

EXAMPLE 88 7-(3-tert-Butyl-1-methylpyrazol-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 28%; mp. 143° C. (methanol)

C₂₀ H₂₄ N₂ O₃ (340): Calculated: 70.57, C; 7.11, H; 8.23, N; 14.10, O. Found: 70.4, C; 7.3, H; 8.1, N; 13.8, O.

EXAMPLE 89 3,4-Dimethyl-7-(1,3-dimethyl-1,2,4-triazol-5-yl)-methoxycoumarin

Yield: 42%; mp. 180° C. (methanol)

C₁₆ H₁₇ N₃ O₃ (299): Calculated: 64.20, C; 5.72, H; 14.04, N; 16.04, O. Found: 64.5, C; 5.9, H; 13.8, N; 15.8, O.

EXAMPLE 90 3,4-Dimethyl-7-(1-methyl-5-nitroimidazol-2-yl)-methoxycoumarin

Yield: 22%; mp. 184° C. (acetone) C₁₆ H₁₅ N₃ O₅ (329): Calculated: 58.36, C; 4.59, H; 12.76, N; 24.29, O. Found: 58.0, C; 4.7, H; 12.6, N; 24.5, O.

EXAMPLE 91 6-Bromo-3,4-dimethyl-7-(1-methyl-5-isopropylpyrazol-3-yl)-methoxycoumarin

Yield: 32%; mp. 177°-179° C. (methanol)

EXAMPLE 92 7-(2-tert-Butylthiophen-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 86%; mp. 137° C. (ethyl acetate)

C₂₀ H₂₂ O₃ S (342): Calculated: 70.15, C; 6.48, H; 14.02, O; 9.36, S. Found: 69.7, C; 6.4, H; 14.2, O, 9.2, S.

EXAMPLE 93 6-Bromo-7-(2-tert-butylthiophen-5-yl)-methoxy-3,4-dimethylcoumarin

Yield: 4.5%; mp. 170° C. (methanol/ethyl acetate)

C₂₀ H₂₁ BrO₃ S (421): Calculated: 50.01, C; 5.02, H; 18.96, Br; 11.39, O; 7.61, S. Found: 56.8, C; 5.0, H; 18.3, Br; 11.5, O; 7.7, S.

EXAMPLE 94 3,4-Dimethyl-7-(2-cyclopropyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

Yield: 62% mp. 143° C. (ethyl acetate) C₁₇ H₁₆ N₂ O₃ S (328): Calculated: 62.18, C; 4.91, H; 8.53, N; 14.62, O; 9.86, S. Found: 61.7, C; 4.9, H; 8.5, N; 14.6, O; 10.0, S.

EXAMPLE 95 3,4-Dimethyl-7-(3,5-dimethylisoxazol-4-yl)-methoxycoumarin

Yield: 53%; mp. 145°-147° C. (methanol)

C₁₇ H₁₇ NO₄ (299): Calculated: 68.22, C; 5.72, H; 4.68, N; 21.38, O. Found: 67.9, C; 5.9, H; 4.5, N, 21.8, O.

EXAMPLE 96 3,4-Dimethyl-7-[3-(1-methylcyclopropyl)-isoxazol-5-yl]-methoxycoumarin

Yield: 64%; mp. 122° C. (methanol)

C₁₉ H₁₉ NO₄ (325): Calculated: 70.14, C; 5.89, H; 4.31, N; 19.69, O. Found: 69.8, C; 5.9, H; 4.3, N; 19.8, O.

EXAMPLE 97 3,4-Dimethyl-7-[3-(tetrahydrofuran-3-yl)-isoxazol-5-yl]--methoxycoumarin

Yield: 48%; mp. 122° C. (methanol)

C₂₀ H₁₉ NO₅ (325): Calculated: 66.85, C; 5.61, H; 4.1, N; 23.43, O. Found: 66.8, C; 5.7, H; 4.1, N; 23.7, O.

EXAMPLE 98 3,4-Dimethyl-7-(3-cyclopentylisoxazol-5-yl)-methoxycoumarin

Yield: 56; mp. 128° C. (methanol)

C₁₉ H₂₀ N₂ O₄ (230) Calculated: 67.05, C; 5.92, H; 8.23, N; 18.89, O. Found: 66.9, C; 6.0, H; 8.1, N; 18.9, O.

EXAMPLE 99 3,4-Dimethyl-7-(3-cyclohexylisoxazol-5-yl)-methoxycoumarin

Yield: 77%; mp. 143° C.

C₂₀ H₂₂₀ N₂ O₄ (354): Calculated: 67.78, C; 6.26, H; 7.90, N; 18.06, O. Found: 67.5, C; 6.3, H; 7.9, N; 18.3, O.

EXAMPLE 100 6-Chloro-3,4-dimethyl-7-(2-pyridinyl)-methoxycoumarin

The procedure and working up were carried out as described under Example 2. In addition, 0.1% of 18-crown-6 was added to the reaction mixture.

Yield: 74%; mp. 201° C. (methanol)

C₁₇ H₁₄ CPNO₃ (316): Calculated: 64.67, C; 4.47, H; 11.23, Cl; 4.44, N; 15.20, O. Found: 64.4, C; 4.6, H; 11.6, Cl, 4.4, N, 15.1, O.

EXAMPLE 101 3,6-Dichloro-4-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-methoxycoumarin

Yield: 19.5%; mp. 216° C. (methanol)

C₁₄ H₁₀ Cl₂ N₂ O₃ S (357) Calculated: 47.07, C; 2.82, H; 19.85, Cl; 7.84, N; 13.44, O; 8.98, S. Found: 46.9, C; 2.9, H; 19.4, Cl; 7.8, N; 13.7, O; 8.9, S.

EXAMPLE 102 6-Bromo-3-chloro-4-methyl-7-(1-methyl-5-isopropylpyrazol-3-yl)-methoxycoumarin

The procedure and working up were carried out similarly to Example 100.

Yield: 46%; mp. 165° C. (methanol)

C₁₈ H₁₈ BrClN₂ O₃ (426): Calculated: 50.79, C; 4.26, H; 18.77, Br; 8.33, Cl; 6.58, N; 11.27, O. Found: 50.2, C; 4.1, H; 18.4, Br; 8.7, Cl; 6.4, N; 11.5, O.

EXAMPLE 103 3,6-Dichloro-4-methyl-7-(2-isopropylthiazol-4-yl)-methoxycoumarin

The procedure and working up were carried out similarly to Example 100.

Yield: 28%; mp. 175° C. (methanol)

C₁₇ H₁₆ ClNO₃ S (385): Calculated: 53.00, C; 4.19, H; 18.40, Cl; 3.64, N; 12.40, O; 8.32, S. Found: 52.8, C; 4.0, H; 18.5, Cl; 3.6, N; 12.5, O; 8.3, S.

EXAMPLE 104 6-Bromo-3-chloro-4-methyl-7-(2-isopropylthiazol-4-yl)-methoxycoumarin

The procedure and working up were carried out similarly to Example 100.

Yield: 22%; mp. 186° C. (methanol)

C₁₇ H₁₆ BrClNO₃ S (428): Calculated: 47.60, C; 3.50, H; 18.60, Br; 8.28, Cl; 3.26, N; 11.20, O; 7.46, S. Found: 47.7, C; 3.6, H; 18.7, Br; 8.4, Cl; 3.2, N; 11.30, O; 7.5, S

EXAMPLE 105 3,4-Dimethyl-7-(3-phenylisoxazol-5-yl)-methoxycoumarin

Yield: 73%; mp. 186° C. (ethanol)

C₂₁ H₁₇ NO₄ (347): Calculated: 72.61, C; 4.93, H; 4.03, N; 18.42, O. Found: 72.6, C; 5.1, H; 3.9, N; 18.4, O.

EXAMPLE 106 3,4-Dimethyl-7-(4-methyloxazol-5-yl)-methoxycoumarin

The procedure and working up were carried out similarly to Example 10.

Yield: 34%; mp. 187° C. (methanol)

EXAMPLE 107 4-Trifluoromethyl-7-(2-methyl-1,3,4-thiadiazol-5-yl)-methoxycoumarin

The procedure and working up were carried out similarly to Example 10.

Yield: 76%; mp. 178° C. (methanol).

A) Tablets having the following composition were pressed on a tabletting press in a conventional manner:

40.00 mg of the substance of Example 108

120.00 mg of corn starch

13.50 of gelatine

45.00 mg of lactose

2.25 mg of Aerosil® (chemically pure silica in the form of submicroscopic particles)

6.75 mg of potato starch (as 6% strength base)

B) 20.00 mg of the substance of Example 75

60.00 mg of core material

The core material consists of 9 parts of corn starch, 3 parts of lactose and 1 part of Luviskol® VA 64 (60:40 vinylpyrrolidone/vinyl acetate copolymer, cf. Pharm. Ind. 1962, 586). The sugar-coating material consists of 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The coated tablets prepared in this manner are then provided with a coating which is resistant to gastric juice. 

We claim:
 1. An alkoxycoumarin substituted by a heterocyclic radical, of the formula: ##STR9## in which R¹ and R² independently of one another are each hydrogen, C₁ -C₅ -alkyl, trifluoromethyl, phenyl or halogen, or together form a C₃ -C₅ -alkylene chain, R³ is C₁ -C₅ -alkyl or halogen, n is an integer of from 0 to 3, R⁴ is hydrogen or C₁ -C₄ -alkyl and Het is ##STR10## wherein R⁵ is unsubstituted or C₁ -C₄ -alkoxy-substituted C₁ -C₁₀ -alkyl, 5-membered or 6-membered oxacycloalkyl, C₃ -C₇ -cycloalkyl, benzyl, a pyridine ring, C₁ -C₅ -alkoxycarbonyl or perfluoro-C₁ -C₂ -alkyl, R⁶ is C₁ -C₅ -alkyl or C₁ -C₅ -alkoxy, R¹¹ is C₁ -C₅ -alkyl, and R¹² is hydrogen, C₁ -C₅ -alkyl or C₃ -C₆ -cycloalkyl.
 2. An oral therapeutic agent which contains, as the active compound, from 10 to 500 mg, per dose, of an alkoxycoumarin substituted by a heterocyclic radical, of the formula ##STR11## in which R¹ and R² independently of one another are each hydrogen, C₁ -C₅ -alkyl, trifluoromethyl, phenyl or halogen, or together form a C₃ -C₅ -alkylene chain, R³ is C₁ -C₅ -alkyl or halogen, n is an integer of from 0 to 3, R⁴ is hydrogen or C₁ -C₄ -alkyl and Het is ##STR12## wherein R⁵ is unsubstituted or C₁ -C₄ -alkoxy-substituted C₁ -C₁₀ -alkyl, 5-membered or 6-membered oxacycloalkyl, C₃ -C₇ -cycloalkyl, benzyl, a pyridine ring, C₁ -C₅ -alkoxycarbonyl or perfluoro-C₁ -C₂ -alkyl, R⁶ is C₁ -C₅ -alkyl or C₁ -C₅ -alkoxy, R¹¹ is C₁ -C₅ -alkyl, and r¹² is hydrogen, C₁ -C₅ -alkyl or C₃ -C₆ -cycloalkyl in addition to conventional pharmaceutical auxiliaries.
 3. A parenteral therapeutic agent which contains, as the active compound, from 1 to 50 mg, per dose, of an alkoxycoumarin substituted by a heterocyclic radical, of the formula ##STR13## in which R¹ and R² independently of one another are each hydrogen, C₁ -C₅ -alkyl, trifluoromethyl, phenyl or halogen, or together form a C₃ -C₅ -alkylene chain, R³ is C₁ -C₅ -alkyl or halogen, n is an integer of from 0 to 3, R⁴ is hydrogen or C₁ -C₄ -alkyl and Het is ##STR14## wherein R⁵ is unsubstituted or C₁ -C₄ -alkoxy-substituted C₁ -C₁₀ -alkyl, 5-membered or 6-membered oxacycloalkyl, C₃ -C₇ -cycloalkyl, benzyl, a pyridine ring, C₁ -C₅ -alkoxycarbonyl or perfluoro-C₁ -C₂ -alkyl, R⁶ is C₁ -C₅ -alkyl or C₁ -C₅ -alkoxy, R¹¹ is C₁ -C₅ -alkyl, and R¹² is hydrogen, C₁ -C₅ -alkyl or C₃ -C₆ -cycloalkyl in addition to conventional pharmaceutical auxiliaries.
 4. An agent for treating neurodegenerative disorders caused by MAO activity which contains, as the active compound, an alkoxycoumarin substituted by a heterocyclic radical, of the formula ##STR15## in which R¹ and R² independently of one another are each hydrogen, C₁ -C₅ -alkyl, trifluoromethyl, phenyl or halogen, or together form a C₃ -C₅ -alkylene chain, R³ is C₁ -C₅ -alkyl or halogen, n is an integer of from 0 to 3, R⁴ is hydrogen or C₁ -C₄ -alkyl and Het is ##STR16## wherein R⁵ is unsubstituted or C₁ -C₄ -alkoxy-substituted C₁ -C₁₀ -alkyl, 5-membered or 6-membered oxacycloalkyl, C₃ -C₇ -cycloalkyl, benzyl, a pyridine ring, C₁ -C₅ -alkoxycarbonyl or perfluoro-C₁ -C₂ -alkyl, R⁶ is C₁ -C₅ -alkyl or C₁ -C₅ -alkoxy, R¹¹ is C₁ -C₅ -alkyl, and R¹² is hydrogen, C₁ -C₅ -alkyl or C₃ -C₆ -cycloalkyl in addition to conventional pharmaceutical auxiliaries.
 5. A method for treating neurodegenerative disorders caused by MAO activity which comprises administering an effective amount of an alkoxycoumarin substituted by a heterocyclic radical, of the formula ##STR17## in which R¹ and R² independently of one another are each hydrogen, C₁ -C₅ -alkyl, trifluoromethyl, phenyl or halogen, or together form a C₃ -C₅ -alkylene chain, R³ is C₁ -C₅ -alkyl or halogen, n is an integer of from 0 to 3, R⁴ is hydrogen or C₁ -C₄ -alkyl and Het is ##STR18## wherein R⁵ is unsubstituted or C₁ -C₄ -alkoxy-substituted C₁ -C₁₀ -alkyl, 5-membered or 6-membered oxacycloalkyl, C₃ -C₇ -cycloalkyl, benzyl, a pyridine ring, C₁ -C₅ -alkoxycarbonyl or perfluoro-C₁ -C₂ -alkyl, R⁶ is C₁ -C₅ -alkyl or C₁ -C₅ -alkoxy, R¹¹ is C₁ -C₅ -alkyl, and R¹² is hydrogen, C₁ -C₅ -alkyl or C₃ -C₆ -cycloalkyl to a human being or animal. 